In the nervous system, the molecular mechanisms of neurotransmitter receptor function and the interactions of alcohols and other neuroactive substances with those mechanisms are poorly understood. This project used a combination of molecular biological and electrophysiological techniques to investigate the molecular structure-function relationships of neurotransmitter receptors and the molecular mechanisms of alcohol and neuroactive substance action on those receptors. Traditionally, cell membrane lipids have been thought to be the primary target of alcohols and volatile general anesthetics, but recent studies have suggested that these agents may interact directly with certain neurotransmitter-gated membrane ion channels. However, the molecular region of the receptor involved in these actions has not been established. Molecular chimeras have been found to be extremely useful for determining structure-function relationships of membrane proteins. A functional chimeric receptor-ion channel has been constructed with the N-terminal domain from the nicotinic acetylcholine (nACh) type alpha 7 receptor and the transmembrane and C-terminal domains from the serotonin (5-hydroxytryptamine) type 3 (5-HT3) receptor (Nature 1993;366:479-83). We studied the effect of ethanol and the volatile anesthetics halothane and isoflurane on the function of these receptors expressed in Xenopus oocytes using voltage-clamp techniques. All three agents inhibited nACh-alpha-7 responses, potentiated 5-HT3 responses, and inhibited the chimeric receptor responses, suggesting that the alcohol and anesthetic action involves the N-terminal domain.